Asymmetric synthesis of bicyclic ketones having an angular substituent via Ti(II) alkoxide-mediated tandem cyclization of trisubstituted olefinic substrates

Article abstract of DOI:10.1021/ol9904038

(Formula Presentation) Angularly substituted, optically active bicyclic ketones of up to 94% ee were prepared by the Ti(II) alkoxide-mediated tandem cyclization of open-chain substrates, that is, 8-phenylmenthyl enynoates having a trisubstituted double bond.

Full text of DOI:10.1021/ol9904038

ORGANIC
LETTERS
2000
Vol. 2, No. 3
381-383
Asymmetric Synthesis of Bicyclic
Ketones Having an Angular Substituent
via Ti(II) Alkoxide-Mediated Tandem
Cyclization of Trisubstituted Olefinic
Substrates
Hirokazu Urabe, Daigaku Hideura, and Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
fsato@bio.titech.ac.jp
Received December 13, 1999
ABSTRACT
Angularly substituted, optically active bicyclic ketones of up to 94% ee were prepared by the Ti(II) alkoxide-mediated tandem cyclization of
open-chain substrates, that is, 8-phenylmenthyl enynoates having a trisubstituted double bond.
Bicyclic ketones having a substituent at their angular position
such as those shown in Figure 1 should be versatile
increasing importance of asymmetric synthesis leads to a
greater demand for chiral building blocks; however, the
preparation of optically active ketones 1-5 has not yet been
reported in the literature. In addition to the conventional
methods, the recently introduced transition metal-catalyzed
or -mediated carbonylative cyclization of enynes provides
an attractive method for preparing a variety of bicyclic
ketones,4-7 including optically active ones.4a,g,6b However,
this process does not appear to be suitable for the preparation
of the above ketones, because the cyclization of 1,1-
disubstituted olefinic substrates, which are precursors for the
angularly substituted ketones, usually requires the presence
Figure 1.
compounds for the preparation of cyclic compounds.1 In fact,
some of these ketones were prepared in racemic form by an
aldol-based method1,2 and utilized as the starting material
for the synthesis of naturally occurring products.3 The
(2) Ramaiah, M. Synthesis 1984, 529-570. Yoshikoshi, A.; Miyashita,
M. Acc. Chem. Res. 1985, 18, 284-290. Hudlicky, T.; Price, J. D. Chem.
ReV. 1989, 89, 1467-1486.
(3) For the synthesis of (()-isocomene and (()-â-isocomene from (()-
1, see: Paquette, L. A.; Han, Y.-K. J. Am. Chem. Soc. 1981, 103, 1835-
1838. Tobe, Y.; Yamashita, T.; Kakiuchi, K.; Odaira, Y. J. Chem. Soc.,
Chem. Commun. 1985, 898-899. For (()-gymnomitrol and (()-gymnomi-
trene from (()-5, see: Welch, S. C.; Chayabunjonglerd, S. J. Am. Chem.
Soc. 1979, 101, 6768-6769. Welch, S. C.; Chayabunjonglerd, S.; Rao, A.
S. C. P. J. Org. Chem. 1980, 45, 4086-4093. See also: Dorsch, M.; Ja¨ger,
V.; Spo¨nlein, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 798-799.
(1) For a review of the utility of five-membered bicyclic ketones, see:
Trost, B. M. Chem. Soc. ReV. 1982, 11, 141-170. Paquette, L. A. In Topics
in Current Chemistry; Boschke, F. L., Ed.; Springer-Verlag: Berlin, 1984;
Vol. 119, pp 1-158. Mehta, G.; Srikrishna, A. Chem. ReV. 1997, 97, 671-
719. Singh, V.; Thomas, B. Tetrahedron 1998, 54, 3647-3692.
10.1021/ol9904038 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/11/2000

of substituents to the tether portion (i.e., steric promotion;8
for example, the assistance by the Thorpe-Ingold effect) to
achieve good yields.4d,6 To find a viable solution, we
reexamined our tandem cyclization of 2,7-enynoates with a
titanium(II) alkoxide as shown in eq 1,9 but this time, we
chose substrates having a trisubstituted olefin. More impor-
tantly, the replacement of the ester portion of the substrate
with an appropriate chiral auxiliary led us to develop an
asymmetric synthesis of 1-5 with high enantiomeric purity.
the tandem cyclization of ethyl esters 11-14 (entries 1-4
in Table 1) nicely proceeded according to eq 1 to give the
Table 1. Preparation of Angularly Substituted
Bicyclo[3.3.0]octenones and Related Reactionsa
The tandem cyclization shown in eq 1 consists of two
steps: step 1 is the formation of titanacycle 8 from enynoates
6 and the titanium(II) reagent (η2-propene)Ti(O-i-Pr)2 (7)
readily prepared in situ from Ti(O-i-Pr)3Cl and i-PrMgCl.10
Step 2 involves the regioselective protonation of 8 with
s-BuOH giving alkenyltitanium species 9, which undergoes
intramolecular attack to the released ester group to give
bicyclic ketone 10.9 As the Group 4 metal (Ti or Zr)-
mediated intramolecular cyclization5 of a trisubstituted olefin
and other carbon-carbon multiple bonds is again a sluggish
process,11 the feasibility of the 7-mediated cyclization to give
titanacycle 8 was a matter of serious concern. Nonetheless,
desired bicyclic ketones 1-4 in good yields. The reactions
of some other relevant substrates are also shown in Table 1.
A trisubstituted olefin of a different pattern such as that in
15 also participated in the cyclization to afford bicyclic
ketone 16 as a single stereoisomer (entry 5). Even tetrasub-
stituted olefinic ester 17 is a possible substrate for this tandem
cyclization to give bicyclic ketone 18, albeit in a moderate
yield (entry 6). However, the cyclization of R,â-unsaturated
lactone 19 stopped at step 1, most likely due to steric bias
in the step-2 cyclization, to afford spirolactone 20 (entry 7).
The favorable interaction between an electron-deficient olefin
with the electron-rich, low-valent titanium center may
account for the success of the step-1 cyclization, as the
replacement of CO2R(*) of 6 with an alkyl group completely
halted the formation of the corresponding titanacycle.7a
(4) (a) Geis, O.; Schmalz, H.-G. Angew. Chem. 1998, 110, 955-958;
Angew. Chem., Int. Ed. 1998, 37, 911-914. (b) Ojima, I.; Tzamarioudaki,
M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635-662. (c) Tamao, K.;
Kobayashi, K.; Ito, Y. Synlett 1992 539-546. (d) Schore, N. E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, pp 1037-1064. (e) Schore, N. E. In Organic
Reactions; Paquette, L. A., Ed.; Wiley: New York, 1991; Vol. 40, pp 1-90.
(f) Sugihara, T.; Yamada, M.; Ban, H.; Yamaguchi, M.; Kaneko, C. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2801-2803. (g) Adrio J.; Carretero, J. C.
J. Am. Chem. Soc. 1999, 121, 7411-7412.
Considering the synthetic importance of the bicyclic
ketones, we then turned our attention to an asymmetric
version of the above process starting with optically active
esters. After trials using several esters derived from chiral
alcohols,12 8-phenylmenthyl esters13 such as 21 in entry 1,
Table 2, were found to give the best result. Under these
conditions, the desired ketone (-)-2 was isolated in good
(5) For a review on the Group 4 metal-mediated cyclization and
carbonylative cyclization, see: Buchwald, S. L.; Nielsen, R. B. Chem. ReV.
1988, 88, 1047-1058. Negishi, E. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp
1163-1184. Broene, R. D.; Buchwald, S. L. Science 1993, 261, 1696-
1701. Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124-130. Maier,
M. In Organic Synthesis Highlights II; Waldmann, H., Ed.; VCH:
Weinheim, 1995; pp 99-113. Ohff, A.; Pulst, S.; Lefeber, C.; Peulecke,
N.; Arndt, P.; Burkalov, V. V.; Rosenthal, U. Synlett 1996, 111-118.
Negishi, E.; Takahashi, T. Bull. Chem. Soc. Jpn. 1998, 71, 755-769.
(6) (a) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 5881-5898. (b) Hicks, F. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 7026-7033.
(11) The successful cases are so far limited to substrates having a nitrogen
atom (coordination effect) or geminal substituents (Thorpe-Ingold effect)
in their tether portion, which are not valid for 6. For a survey on the outcome
of the cyclization of polysubstituted olefins with Group 4 metal reagents,
see: ref 6. Negishi, E.; Maye, J. P.; Choueiry, D. Tetrahedron 1995, 51,
4447-4462. Yamaura, Y.; Mori, M. Tetrahedron Lett. 1999, 40, 3221-
3224.
(7) (a) Urabe, H.; Hata, T.; Sato, F. Tetrahedron Lett. 1995, 36, 4261-
4264. (b) Urabe, H.; Takeda, T.; Hideura, D.; Sato, F. J. Am. Chem. Soc.
1997, 119, 11295-11305.
(8) Sammes, P. G.; Weller, D. J. Synthesis 1995, 1205-1222.
(9) (a) Suzuki, K.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 1996, 118,
8729-8730. (b) Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997,
119, 10014-10027.
(12) See Supporting Information.
(13) Whitesell, J. K. Chem. ReV. 1992, 92, 953-964. Jones, G. B.;
Chapman, B. J. Synthesis 1995, 475-497. Seyden-Penne, J. Chiral
Auxiliaries and Ligands in Asymmetric Synthesis; Wiley: New York, 1995;
p 513. Regan, A. C. J. Chem. Soc., Perkin Trans. 1 1999, 357-373.
(10) Sato. F.; Urabe, H.; Okamoto, S. J. Synth. Org. Chem., Jpn. 1998,
56, 424-432.
382
Org. Lett., Vol. 2, No. 3, 2000

ketone 2 (91-93% ee), suggesting that the kinetic resolution
at step 2 should contribute to the further enhancement of
the de value resulting from step 1. However, the forcing
cyclization conditions in step 2 (a higher temperature and/
or a longer reaction period) to promote the yield of 2 were
totally ineffective. Thus, irrespective of a subtle change in
the reaction conditions, the enantiopurity of the bicyclic
ketone remains constant, the reproducibility being guaran-
teed.14
Table 2. Preparation of Optically Active
Bicyclo[3.3.0]octenonesa
The preparation of a series of optically active bicyclic
ketones 1-4 from the corresponding 8-phenylmenthyl esters
21 and 25-27 is summarized in Table 2. Silyl derivative
(-)-3 was smoothly desilylated with Bu4NF to give (R)-5
(Figure 1) without loss of the enantiopurity (80% yield).
Subsequent hydrogenation of (R)-5 (H2, Pd/C) afforded the
known (-)-(1R,5S)-1-methylbicyclo[3.3.0]octan-3-one (80%
yield),15 which unambiguously determined the absolute
configuration of (-)-3 to be R. The absolute stereochemistry
of the other products was deduced by analogy based on the
same sign of their optical rotations. The documented stere-
ochemical control in 8-phenylmenthyl esters,13 namely, that
the phenyl ring blocks one side of the plane of the conjugated
π-system of the R,â-unsaturated carbonyl moiety as il-
lustrated with 28 in Figure 2, is consistent with the observed
absolute stereochemistry of the products. The eliminated
8-phenylmenthol was recovered after the cyclization in a
nearly quantitative yield (for instance, entry 1) and may be
recycled. It should be noted that this method achieved the
first preparation of the optically active bicyclic ketones 1-5
(Figure 1). The above results have brought about a novel
phase of the 7-mediated cyclization of bis-unsaturated
compounds, and its further application to asymmetric syn-
thesis will be reported in due course.
yield and with high enantiopurity. This result deserves the
following two comments. First, the step-2 cyclization of the
relatively hindered ester 21 was notably promoted by the
presence of the â-methyl group to the ester, because substrate
22 lacking the vinylic methyl group in 21 did not undergo
the cyclization of step 2, merely giving monocyclic ester 23
(entry 2, Table 2). The latter observation is in accord with
our earlier result that a similar tert-butyl ester does not
undergo step 2 at all.9b Second, monocyclic ester 24 (Figure
2) was separated as a byproduct (30% yield) and its de value
(42% de) was considerably lower than the ee of bicyclic
Acknowledgment. We thank the Ministry of Education,
Science, Sports and Culture (Japan) and, in part, a Sankyo
Award in Synthetic Organic Chemistry (to H.U.) for financial
support.
Supporting Information Available: Procedure for the
preparation of the starting material 21 and bicyclic ketone
(-)-2, characterization data for the starting materials and
products, and an addendum to Table 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9904038
(14) Although the clear explanation needs more experimental support,
the different site selectivities of the protonation (to vinyl-Ti vs R-ester-Ti
bonds) dependent upon the diastereomeric titanacycles 8 (eq 1) may account
for this phenomenon.
(15) Castro, J.; So¨rensen, H.; Riera, A.; Morin, C.; Moyano, A.; Perica´s,
M. A.; Greene, A. E. J. Am. Chem. Soc. 1990, 112, 9388-9389. Greene,
A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26, 5525-5528.
Figure 2.
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